Malaria is one of the world's leading killer infectious diseases. Although almost a third of the Earth's population is considered to be at risk from this disease, about 90% of infections and deaths occur in Africa (Trigg, P. I., and Wernsdorfer, W. H., Parasitologia: (1999) 41, 329-332), contributing significantly to underdevelopment and poverty on this continent (Gallup, J. L., and Sachs, J. D., Am. J. Trop. Med. Hyg: (2001) 64s, 85-96). The estimated 300 million cases that occur per year result in considerable morbidity (e. g. fever, malaise, anorexia, anemia) and mortality of over 2 million children under age group of five (World malaria situation in 1994 part I. Wkly Epidemiol rec: (1997) 72, 269-274. The intracellular protozoal parasite Plasmodium falciparum, accounts for greater than 95% of the malarial deaths. An important contributor to the increase in incidence of malaria over the past 30 years has been the development of resistance of the malarial parasite to quinoline containing antimalarials such as chloroquine and quinine (Barat, L. M., and Boland, P. B., Drug resistance among malaria and other parasites. Infet Dis Clin North Am: (1997) 11 (4), 969-987). In addition, it has been recognized that a number of complications, such as anemia, failure to gain weight and immunosuppression associated with malaria infection continue to occur for weeks and over months after the parasites are cleared from the body (Ho, M., Webster, H. K., and Looareesuwan, S. Antigen-specific immunosuppression in human malaria due to plasmodium falciparum. J. Infect Dis: (1986) 153, 763-771; McGregor, A., and Barr, M. Antibody response to tetanus toxoid inoculation in malarious and non-malarious Gambian children. Trans R Soc Trop Med hyg: (1962) 56, 364-367; Bradley-Moore, A. M., Greenwood, B. M. and Bradley, A. K. Malaria chemoprophylaxis with chloroquine in young Nigerian children. II. Effect on immune response to vaccination. Ann Trop Med Parasitol: (1985) 79, 563-573). For the majority of their life-cycle in humans, malaria parasites live in red blood cells. Within the erythrocytes, the parasites feed on hemoglobin, digesting the protein and releasing the heme. The heme which is released as the by-product of hemoglobin is toxic compound to the parasite. The malarial parasite having a unique heme detoxication mechanism that the heme is converted to non-toxic heme polymer hemozoin (malaria pigment) within the food vacuole (Rudzinska, M. A., Trager, W. and Bray, R. S. Pinocytic uptake and the digestion of hemoglobin in malaria parasites. J. Protozool: (1965) 12(4), 563-576). Trager, W; Jensen, J. B. Science, (1976), 193, 674) that serves to protect the parasite from potentially toxic free heme, as well as to induce pathology in the infected host. Overtime, the intraerythrocytic parasite exhausts this energy and protein supply and then begins next stage of life cycle. Through a series of DNA and membrane divisions, trophozoites converted to mature schizonts. Schizonts-containing erythrocytes rupture, each releasing 6 to 24 merozoites and one large ‘garbage bag’ containing polymerized hemozoin. It is this process that produces febrile clinical attack. The released merozoites invade more erythrocytes to continue the cycle, which proceeds until death of the host or modulation by drugs or acquired immunity. The 2-chloropyridine based Baylis Hillman adducts and 4-quinolino-methanols are reported to be antimalarial agents. These classes of compounds are particularly acting on erythrocytic stage of the parasite.
The following references are examples for the synthesis of and biological evaluation of some of the antimalarial agents. These prior arts contain useful information and discussion on the preparation and properties of antimalarial agents.
U.S. Pat. No. 6,627,641 (2003) reported the synthesis and use of naphthylisoquinoline alkaloids and their pharmaceutical formulation as efficient antmalarial agents.
U.S. Pat. No. 6,479,660 (2000) reported the synthesis and use of quinoline compounds as antimalarial drugs.
Sujatha, V. B. et. al. Bioorg & Med. Chem. Lett, 9, 731-736 (1999) reported the antimalarial activity of 3-hydroxy alkyl-2-methylene-propionic acid derivatives.
U.S. Pat. No. 6,689,777 (2004) reported the synthesis of novel substituted naphthothiozolium, aromatic guanylhydrazones and other compounds and compositions having antimalarial activity.
Donald J. Krogstad. et al., Science, 238, 1283-1285 (1987) reported the mechanism of chloroquine resistance in plasmodium.
U.S. Pat. No. 6,693,217 (2004) reported the synthesis of N, N1-substituted asymmetrical imidodicarbonimidic diamides as antimalarial agents.
Arnulf Dorn et al., Nature 374, 269-371 (1995) reported the process of heme polymerization and mechanism of action of chloroquine.
U.S. Pat. No. 2004/0180913 (2004) reported the synthesis of 2,4-diaminopyrimidine derivatives and their use as antimalarial agents by inhibiting dihydrofolate reductase (DHFR-Inhibitors)
Christian Segheraert. et al. J. Med. Chem. 46, 542-547 (2003) reported the synthesis and antimalarial activity of N1-(7-chloro-4quinolyl)-1,4bis(3-aminopropyl) piperazine derivatives.